Patients with lesions in the orbitofrontal cortex display characteristic behavioral deficits in various decision- making tasks. They are impaired in revising their behavioral strategies when the previously advantageous actions no longer produce desirable outcomes and integrating multiple dimensions of the decision outcomes to make optimal choices. These behavioral changes resemble the symptoms of drug addicts who are unable to discontinue the use of abused substance that are no longer pleasurable and lead to negative consequences. Dysfunctions of the orbitofrontal cortex are also implicated in many mood and anxiety disorders. In addition, patients with orbitofrontal lesions are unable to take into consideration hypothetical outcomes from unchosen actions to improve their decision-making strategies. Despite this wide clinical implication of the orbitofrontal dysfunctions, the nature of specific computational steps embodied in the orbitofrontal cortex and disrupted in many mental disorders is unknown. Studies proposed in this application will investigate how multiple reward- related parameters and various decision variables are encoded and integrated by individual neurons of the primate orbitofrontal cortex. First, we will test whether the neurons in the orbitofrontal cortex will integrate multiple reward parameters during an inter-temporal gambling task in which the magnitude, delay, and uncertainty of reward available from each option is systematically manipulated. Second, we will investigate whether neurons in different subdivisions of the orbitofrontal cortex tend to specialize in propagating the signals related to positive and negative outcomes. This will be tested in a token-based decision-making task in which the animal's choice behaviors are reinforced and punished by the delivery and removal of conditioned reinforcers, respectively. Finally, we will also test whether the information about the hypothetical outcomes from unchosen actions are reflected and integrated with the signals related to the animal's choices in the activity of orbitofrontal neurons. The results from these experiments will elucidate how the signals originating from different sources are integrated and transformed in the orbitofrontal cortex so that they can be used directly to guide the animal's choices. Accordingly, the proposed studies will contribute to prevention and more efficient treatment strategies for substance abuse and other mental disorders that involve the orbitofrontal cortex.

Public Health Relevance

Lesions and abnormal activity in the orbitofrontal cortex produces a variety of behavioral impairments, often highlighted by the failures in adaptively learning the optimal decision-making strategies. Accordingly, orbitofrontal dysfunctions are implicated in drug addiction and other psychiatric disorders, including anxiety and mood disorders. Combining a series of novel behavioral tasks and multi-channel neurophysiological recordings, the proposed studies will elucidate the cellular basis for information processing in the orbitofrontal cortex and contribute to improving diagnosis and treatment strategies for many mental illnesses.